Hydroxyphenethyl-amino-s-triazine



United States Patent 3,274,190 B-HYDROXYPHENETHYL-AMDSIO-s-TRIAZINEAllan Poe Gray and Donald Elmer Heitmeier, Decatur,

IlL, assignors to Neisler Laboratories, Inc., Decatur, Ill., acorporation of Delaware No Drawing. Original application Oct. 30, 1961,Ser. No. 148,716, now Patent No. 3,192,216, dated June 29, 1965. Dividedand this application May 12, 1965, Ser. No. 458,514

3 Claims. (Cl. 260-2495) This invention relates to compositions ofmatter classified in the art of chemistry as N-substitutedfl-aralkylamines and processes for making and using such compositions.This application is a division of application S.N. 148,716, filedOctober 30, 1961, now US. Patent 3,192, 216, which is acontinuation-in-part of application S.N. 66,431, filed November 1, 1960,now abandoned.

The invention sought to be patented, in its composition aspect, isdescribed as residing in the concept of a chemical compound having amolecular structure in which there is attached, to the amino nitrogenatom of a B-hydroxyphenethylamine, a polyhetero-monocyclicaryl moietyhaving five or six ring atoms, two or three of which are hetero atomsconsisting of one of three nitrogen atoms and not more than one oxygenatom and not more than one sulfur atom, by a ring atom of said moiety.Such compositions will hereinafter be identified as N-(polyhetero-monocyclicaryl -fi-hydroxyphenethylamines.

The invention sought to be patented, in the process of making aspect,resides in the concept of embodying such a molecular structure intangible form by linking a polyhetero-monocyclicaryl moiety and a,B-hydroxyphenethyl group through an otherwise unsubstituted trivalentnitrogen atom by (1) the reaction of a polyhetero-monocyclicarylaminewith (a) a styrene oxide or (b) a styrene halohydrin, or (c) aphenylglycolic acid derivative with subsequent reduction of theresultant amide with a suitable reducing agent; or, alternatively, by(2) the reaction of the halide, thiol, thioether or methyl sulfonederivative of a polyhetero-monocyclicaryl compound with afl-hydroxyphenethylamine.

The invention sought to be patented, in the process of using aspect, isdescribed as residing in the concept of using the tangible embodiment ofa composition of matter identified as anN-(polyhetero-monocyclicaryl)-B-hydroxyphenethylamine, by administeringto a human being such composition as the essential active ingredient ofa pharmaceutical formulation for the application of the relief of painto human beings.

The tangible embodiments of the composition aspect of the invention intheir free base form are white crystalline solids; have low aqueoussolubility; and, are soluble in polar organic solvents, for example,lower aliphatic alcohols. Examination of the compounds producedaccording to the herein described process reveals physicalcharacteristics such as ultraviolet and infrared spectra and pKa valueswhich are compatible with the structure of the compositions herein setforth. The aforementioned physical characteristics, taken together withthe nature of the analytical results, starting materials and the mode ofsynthesis, are in accord with the structure of the compositions soughtto be patented.

The tangible embodiments of this invention all possess the inherentapplied use characteristic of relieving pain in animal organisms.Standard pharmacological evaluations indicate the compounds to beuseful, as well, as muscle relaxants, analgesics, sedatives,tranquilizers, or anti-inflammatory agents. A common result of the useof substances having such properties is that of the relief of painassociated with the conditions indicated. In addition, some of thecompounds possess central nervous system stimulant and anorexigenicactivity.

The free base compounds of the persent invention have the generalizedstructure wherein Het represents a polyhetero-monocyclicaryl moiety andR represents hydrogen, lower-alkyl, benzyl, and phenyl, and R representsH and methyl.

As used herein, the term lower-alkyl means alkyl radicals having 1 t0 4carbon atoms, inclusive, ei-ther straight or branched chain, among whichare, for purposes of illustration, but without limiting the generalityof the foregoing, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl,secondary-butyl, and tertiary-butyl.

The term "polyhetero-monocyclicaryl, as used herein, means a monocyclicring system containing five or six essentially coplanar ring atoms, twoor three of which must be hetero atoms, of the formula C N X where Xrepresents a bivalent oxygen or sulfur atom, where m is at least 2 andnot more than 4, n is at least 1 and not more than 3, and, y is not morethan 1; the nucleus of said ring system possessing 6 pi electrons. Thepresence of 6 pi electrons in a monocyclic coplanar ring system is afundamental quantum mechanical criterion of aromaticity as tought in themodern textbooks of organic chemistry. See, for example, the treatmentby G. A. Wheland in his book Resonance in Organic Chemistry, John Wileyand Sons, New York (1955), especially at pages 144 through 147. Forpurposes of illustration, but without limiting the generality of theforegoing, the imidazole, isoxazole, oxadiazole, oxazole, pyrazole,thiadiazo'le, thiazole, triazole, triazine, pyrimidine, pyridazine andpyrazine rings have six pi electrons participating in resonanceinteraction in. the ring system.

The above definition of polyhetero-monocyclicaryl may be summarized bydescribing polyhetero-monocyclicaryl as an aromatic radical containingfive to six ring atoms, two to three of which must be heteroatoms.Implicit in this definition are all of the attributes hereinabovedescribed, i.e., the coplanar monocyclic ring system containing 6 pielectrons. The ring systems meeting these requirements are known tothose skilled in the art of organic chemistry.

The phenyl moiety and the polyhetero-monocyclicaryl moiety include, forpurposes of illustration but without limiting the generality of theforegoing, as the full equivalent of each, respectively, theunsubstituted phenyl radical and the unsubstitutedpolyhetero-monocyclicaryl radical, and such radicals bearing on thering, in place of a hydrogen atom or atoms, one or more simplesubstituents not adversely affecting the hereinbefore describedpharmacological properties of the above generalized structure, such ashalo (see Examples 18, 20, 26, 42), loweralkyl (see Examples 5, 23, 24,41, 50), lower-alkoxy (see Examples 16, 19, 2.5), methylenedioxy, amino(see Examples 22, 40, 45), nitro (see Example 22), trihalomethyl (seeExample 21), hydroxy (see Examples 17, 38), mercapto (see Example 36),lower-alkylthio (see Example 37), carboxy (see Example 27), and othergroups commonly used in the art as aromatic substituents.

Any oxy derivative convertible to a hydroxy compound of the presentinvention after introduction into an animal organism is regarded by theinventors as the full equivalent of the compounds as represented in theabove generalized structure. Oxy derivatives intended to be includedare, for purposes of illustration but without limit- I ing thegenerality of the foregoing: esters which are produced from the hydroxycompounds of this invention and 7 an aldehyde or ketone. Acids fromwhich ester derivatives of the compounds of this invention can bederived include, for purposes of illustration but without limiting thegenerality of the foregoing: lower-alkanoic acids (see Examples 30 and32), formic acid (see Example 31), and alkoxy and alkylthiolformic acids(see Examples 33 and 34), benzoic acid, carbamic acids (see Example 28),N- benzylcarbamic acid and nicotinic acid and lower-alkanedioic acids(see Example 29). Aldehydes and ketones from which oxazolidinederivatives can be derived include, for purposes of illustration butwithout limitation, formaldehyde (see Example 35), acetaldehyde, acetoneand methyl ethyl ketone.

The point of attachment of the fl-hydroxy-phenethyl amino side chain tothe polyhetero-monocyclicaryl group must be to an available carbon ornitrogen position. The preferred point of attachment is to a carbon atomwhich is adjacent to a nitrogen atom of the heterocyclic ring whichwould include: the 2, 4, and positions of the imidazole; the 2 and 4positions of the oxazole, pyrimidine and thiazole rings; the 2 positionin the 1,3,4-oxadiazole and 1,3,4-thiadiazole rings; the 3 position ofisoxazole and isothiazole rings; the 3 and 5 positions of the pyraz-olering; the 4 position of .the 1,2, 3-triazine ring; the 3, 5 and 6positions of the 1,2,4-tri-azine ring; the 3 position of the pyridazinering; and, the 2 position of the pryazine ring.

For purposes of illustration, but without limitation, the ,B-carbon towhich the phenyl moiety is attached has been further substituted by anethyl radical (see Example 14), and a phenyl radical (see Examples 15and 16), and the a-carbon of the ethyl chain has been substituted by amethyl radical (see Example 13). The embodiments of such structuralconcepts have been tested and found to exhibit the same usecharacteristics as asserted herein for the embodiments of the aforesaidfundamental concept and are to be considered full equivalents of thisconcept.

Representative N-(polyhetero-monocyclioaryl)- 3 hydr-oxyphenethylaminesthat are suitable examples of the composition aspect of this inventioninclude for purposes of illustration, but without limitation:

2-(B-hydroxy-fl-methylphenethylamino) -1,3,4- hiadiazole;

3 li-hydroxyphenethylamino -4-methylpyrazo1e;

2- (,B-hydroxy-3 ,4-methylenedioxyphenethylamino) oxazole 3-B-hydroxy-fi-phenyl-4-aminophenethylamino 1,2,4-

oxadiazole;

4- 8-hydroxy-B-ethylphenethylarnino) -2-methoxyimidazole;

3- (B-hydroxyphenethylamino isoxazole;

2- (,B-hydroxy-fl-n-butylphenethylamino) -5-aminothiazole;

3 B-hydroxy-4-chlorophenethylamino) -5-methylthio- 1,2,4-triazole;

2- S-hydroxy-B-n-butylphenethylamino -thiazole;

4-(B-hydroXy-B-isopropylphenethylamino) -1,2,3-triazine;

2- (13-hydroxy-4-trifluoromethylphenethylamino -striazine.

Synthesis of the N-(polyhetero-rnonocycliaryl)phydroxyphenethylarninesof the present invention may be described as a process in which apolyhetero-monocylicaryl moiety is linked with an appropriate,B-hydroxyphenethyl group through an otherwise unsubstituted trivalentnitrogen atom which may be pre-attached to either of the groups to belinked. This generalized process is illustrated by: (1) the reaction ofa polyhetero-mono- 4, cyclicaryl derivative with an appropriate,G-hydroxyphenethylamine H OH Het-Z I-CH-(i'J-phgnyl OH HetN C H-JJ-phenyl N la I l wherein Z=halo, mercapto, lower-alkylthio andmethylsulfonyl, R, R and Het have the same meaning as in the abovegeneralized Structure 1;

(2) by reaction of a polyhetero-monocyclicarylamine with an appropriatestyrene oxide or a potential styrene oxide such as halohydrin:

Q=halogen and R and Het have the same meaning as in the abovegeneralized Structure I;

and (3), by reaction of a polyhetero-monocycliearylamine with aphenylglycolic acid esterifying agent, to yield an amide and subsequentreduction of the amide:

where R=H or acyl, A=halo, hydroxy, acyloxy or alkoxy and R and Het havethe same meaning as in the above generalized Structure 1.

In the above described syntheses, it will be apparent to those skilledin the art of chemistry that the proportion of reactants, duration ofreaction, solvents, acid acceptors, catalysts, etc., can be varieddepending on the type of reactant.

From the specific reaction conditions given in Examples 7-8, 13-17,19-26, 36, 40-42 and 45, it will be obvious to those skilled in the artof chemistry that the reagents and conditions which can be employed inthe inventive process of reaction (1) will depend almost entirely on thenature of Het-Z. However, the following will illustrate the generalrange of reagents and conditions which are useful:

Solvents.Hydrocarbon solvents such as benzene, toluene and xylene;alcohols and aqueous alcohols; and other polar solvents, such asacetone, water, acetonitrile and dimethylformamide; or, the reaction maybe carried out in the absence of solvent.

Acid acceptors.None, when Z equals mercapto and alkylthio; otherwise: atleast one equivalent excess of the B-hydroxyphenethylarnine; hinderedtertiary amines such as triethylamine, tripropylamine, tributylamine,disopropylethylamine; and, inorganic bases such as sodium carbonate,potassium carbonate, sodium hydroxide and potassium hydroxide.

Temperature.Reaction temperatures may range up to 200 degreescentigrade.

Catalysts.-Occasionally a catalyst is required, such as copper powder,cupric salts, sodium iodide and potassium iodide.

In general, it is preferred that the process of reaction (2) be carriedout in the presence of at least one equivalent of a strong basic reagentas illustrated in Example 47. The basic reagent converts thepolyhetero-monocyclicarylamine to its anion which is the species thatundergoes the reaction with styrene oxide. The range of reagents andconditions which can be used are illustrated by the following:

Basic condensing agents.-Sodium amide, potassium amide, lithium amide,butyl lithium, phenyl lithium, sodium hydride and lithium hydride,sodium ethoxide or potassium t-butoxide.

Solvents-(a) When the basic amides are used: Liquid ammonia; ethers suchas ethylene glycol dimethyl ether, tetrahydr-ofuran, mixtures oftetrahydrofuran with the other solvents, and dioxane; benzene andtoluene. (b) When the basic alkoxides are used: Alcohols; and ethersillustrated by those above. (c) When phenyl lithium, butyl lithium .andthe hydrides are used: Ethers as illustrated above and ethyl ether.

Temperature.Reaction temperatures can range between -30 degrees and 150degrees centigrade.

Although it would be expected that substitution of the ring nitrogenwould occur in the absence of a basic agent, it has been an unexpectedfind-ing that a certain limited number ofpolyhetero-monocyclicarylamines can be caused to react with a styreneoxide or styrene halohydrin, in the absence of any basic condensingagent, to yield the N- (polyhetero-monocyclicaryl),B-hydroxyphenethylamines of the invention. For this reaction to proceedas desired, the polyheteromonocyclicarylamine must be selected from thegroup consis ing of 2- and 4-aminopyrimidine, amino-striazine andZ-aminothiazole. This novel process, which apparently involves initialsubstitution at the ring nitrogen followed by ring opening andrearrangement, provides the end product more conveniently, and inreasonable yield, as shown in Examples 9-11 and 18. To illustrate, a 32percent yield of 2-(B-hydroxyphenethylamino)-pyrimidine can be obtainedby reaction of Z-aminopyrimidine with styrene oxide in the absence of abasic reagent (see Example 10), Where as a maximum yield of 5 percent ofthe same product was obtained when the general reaction of process (2)was performed using the Z-aminopyrimidine anion produced by reactionwith sodamide. The general range of reagents and conditions which can beused are illustrated as follows:

Catalysts.A catalytic amount of acid can be used, but neither acid orbasic catalysts are necessary.

Slvents.-No solvent; solvents such as alcohols, dimethylformamide,acetone, acetonitrile.

T emperatwre.Reaction temperatures may vary between 30 and 180 degreescentigrade.

The preferred conditions involve the boiling of the reactants in alcoholfollowed by the heating of the crude product mixture at 100-150 degreesfor 2 to hours (see Example From the specific reaction conditions givenin Examples 1-6, 12, 46 and 48-5 1 it will be obvious to one skilled inthe art that the reagents and conditions which can be employed for theamide formation in the inventive process of reaction (3) will depend onthe nature of the phenylglycoly-l acylat'mg agent used. However, thefollowing will illustrate the general range of reagents and conditionswhich are useful.

(I) When A equals hydroxy:

Solvents: No solvent, benzene, toluene or xylene. Temperature: Reactiontemperatures may range between 30 and 200 degrees centigrade. (II) WhenA equals halo:

Solvents: Benzene, toluene, xylene, pyridine and ether.

Acid acceptors: At least one equivalent excess ofpolyhetero-monocyclioarylamine, pyridine, diisop-ropylethylamine,triethylamine, tripropylamine and tributylamine, sodium carbonate, orsodium hydroxide.

Temperature: Reaction temperatures may range between 0 and degreescentigrade.

(III) When A equals acyloxy:

Solvents: None, or as in II.

Acid acceptors: None, or, as in H.

Temperature: Reaction temperatures may range between 0 and degreescentigrade.

(IV) When A equals lower-alkoxy:

Solvents: Ether, dimethyl ethylene glycol, tetrahydronaphthalene.

Base catalysts: None; or a trace of sodium, potassium or lithium metal,sodium hydride, or sodium amide.

Temperature: Same as (I).

Reduction of the amide with lithium aluminum hydride can be performedusing the general range of reagents and conditions illustrated by thefollowmg:

Solvents: Ether, dimethyl ethylene, glycol, tetrahydro furan, diglyme,dioxane, pyridine, benzene-ether.

Temperature: The reaction temperature can range between 0 and 150degrees centigrade.

Other agents are known to those skilled in the art of organic chemistryfor reducing amides, and, from the foregoing illustration it will beapparent such other agents can be employed to reduce the amide to the N(polyheteromonocyclicaryl)-fl-hyd-roxyphenethylamines of this invention,as the full equivalent of the lithium aluminum hydride, hereinbeforedescribed. Reducing agents intended to be included are, for purposes ofillustration, but without limiting the generality of the foregoing: acombination of aluminum hydride and aluminum chloride; a combination ofsodium borohydride and aluminum chlorodial koxide; sodium and butanol;and, electrolytic reduction.

Polyhetero-monocyclica-ryl reactants which can be used in theappropriate processes are exemplified by the following:

2-halopyrazine 2-, 4- and S-haloimidazole 3-halopyridazine3-haloisoxazole 3-haloisothiazole 2-halo-1,3,4-oxadiazole 3- andS-halo-l,2,4-oxadiazole 4-halo-1,2,3-ox adiazole 2- and 4-halooxazole 3-and 5-4halopyrazole 2-h-alo-l,3,4-thiadiazole 3- and5-halo-l,2,4-thiadiazole 4-halo-1,2,3-thiadiazole 3- and5-halo-l,2,4-triazole 4- and 5-halo-1,2,3-triazole 2-halo-s-triazine 3-,5- and 6-halo-1,2,4-triazine 4-halo-1,2,3-triazine wherein halo ischloro, bromo and iodo. 'l he corresponding amino, thio, methylsulfonyland lower-alkylthio derivatives can be used in the appropriateprocesses.

B-Hydroxyphenethylamine reactants which can be used in the appropriateprocesses are exemplified by the following:

,B-hy-droxyphenethylamine ,B-hydroxy-pfi-diphenylethyilamineB-hydroxy-;8-ethylphenethylamine B-hydroxy-fi-benzylphenethylamineB-hydroxy-B-s-butylphenethylamine3-l1ydroxy-4-trifiuoromethylphenethylamine,B-hydroxy-4-methoxyphenethylamine ,B-hydroxy-4-hydroxyphenethylamine 7B-hydroxy-3 hydroxyphenethylamine fi-hydroxy-B,4-dihydroxyphenethylamine,B-hydroxy-3,4-methylenedioxyphenethylamine {3-hydroxy-2-methyl3,4-dihydroxyphenethylamine Styrene oxide or potential styrene oxidereactants which can be used in the appropriate processes are exemplifiedby the following:

styrene oxide 4-chlorostyrene oxide 3,4-dichlorostyreneoxide4-acetamidostyrene oxide B-hydroxyphenetlhyl chloride Phenylglycolicacid derivatives which can be used in the appropriate processes areexemplified by the following:

O-acetylmandelic acid anhydride O-acetylmandelyl chlorideO-butyryl-p-trifluoromethylmandelyl chloride a-butylmandelic acidO-propionyl-p-nitrom-andelyl chloride p-methyhnandelyl chloride methylbenzilate tbenzilic acid anhydride All the reactants are known compoundsor can be prepared by known methods.

The hydroxy compounds of this invention can be converted to their esterderivatives with a suitable esterifying agent. Such agents employed are:acids, such as formic acid; acyl chlorides, as benzoyl chloride, ethylchloroformate and ethyl chlorothiolformate; alkanoic anhydrides, asacetic anhydride, propionic anhydride and butyric anhydride;lower-alkane-di-oic anhydrides, as succinic anhydride and maleicanhydride; potassium cya nate; lower-alkylisocyanates, as methyl, ethyl,propyl and butyl isocyanates; N,N-dialkylcarbamyl chlorides, as N,N-dimethyl-, N,N-diethyland N,N-di|isopropylca-rbarnyl chloride.

Alternatively, the carbamate esters of the N-(polyhetero-monocyclicaryl) {3 hydroxyphenethylamines of this inventioncan be formed by reacting an hydroxy substituted N(polyhetero-monocyclicaryl)-phenethylam-ine with phosgene and treatingthe intermediate with ammonia or a suitable primary or secondary amine.

The free bases can be used as such or in the form of their crystallineacid addition salts. The acid addition salts are the full equivalents ofthe free bases, and can be prepared by reacting the corresponding freebase in a conventional manner with an inorganic acid as hydrochloric,hydrobromic, sulfuric and phosphoric; or an organic acid, asmethanesulfonic, ethanesulfonic, ethanedisulfonic, cyclohexylsulfarnic,for-mic, maleic, citric, tartaric, and tannic acids.

The manner of making and using the'compositions and processes of ourinvention is further illustrated by the following examples, which setforth the best mode contem plated by us of carrying out the invention soas to enable any person skilled in the art of chemistry to make and usethe same.

The temperatures herein stated are in degrees centigrade.

Example 1.-2(O-acetylmandelamido)-thiaz0le A solution of 42.5 grams (0.2mole) of acetylmandelyl chloride in 100 milliliters of dry ether isadded dropwise to a cold, stirred solution of 20.0 grams (0.2 mole) of2-aminothiazole and 20.5 grams (0.2 mole) of triethylamine in 250milliliters of dry ether. After the addition is complete, the reactionmixture is stirred for 2 hours longer as it warms to room temperature.The precipitated solid is washed with water and then crystallized fromisopropyl alcohol to give 39 grams or an 83 percent yield of2-(O-acetylmandelamido)-thiazole melting at 148-149 degrees.

treated versus the control animals.

8 Analysis-Calculated for C13H12N2O3S: c, 56.51; H, 4.38; S, 11.60.Found: C, 56.68; H, 4.26; S, 11.51.

Example 2.2-(O-acetylmandelamino) -1,3,4-

thiadiazole A solution of 15.0 grams (0.15 mole) of Z-amino-1,3,4-thiadiazole and 34.0 grams (0.16 mole) of acetylrmandelyl chloridein 250 milliliters of dry pyridine is stirred for 2.5 hours at roomtemperature. Concentration of the solution leaves a thick viscous oilwhich is dissolved in chloroform. The chloroform solution is washed withWater, dried, and the chloroform removed in vacuo to yield a thick glasswhich is crystallized from isopropyl alcohol to give 35.8 grams or an 86percent yield of 2-(O-acetylmandelamido)-1,3,4-thiadiazole, melting at179-180 degrees.

Analysis.--Calculated for C H N O S: C, 51.96; H, 4.00; S, 11.55. Found:C, 52.14; H, 4.17; S, 11.60.

Example 3.3-mandelamid0-1,2,4-triaz0le In a flask fitted with a stirrerand a Dean-Stark moisture trap is placed 20.2 grams (0.24 mole) of3-amino- 1,2,4-triazole, 37.0 grams (0.24 mole) of mandelic acid andmilliliters of xylene. The mixture is stirred and heated in an oil-bathat a bath temperature of -180 degrees for 9 hours during which time 4.2milliliters or a 97 percent yield of water is collected. The brownprecipitate is removed from the cooled reaction mixture and the motherliquor diluted with hexane to give an additional small amount ofmaterial. Crystallization of the combined precipitates from methanolafl'ords 36.8 grams or a 71 percent yield of3-mandelamido-l,2,4-triazole melting at 216-217 degrees.

Analysis.Calculated for C H N O C, 55.02; H, 4.62; N (basic), 6.42.Found: C, 55.04; H, 4.81; N basic), 6.39.

Example 4 .-4-mandelamid0-1 ,2,4 -triazole Essentially as described inExample 3, 12.5 grams (0.15 mole) of 4-amino-1,2,4-triazole is reactedwith 22.8 grams (0.15 mole) of mandelic acid in 150 milliliters ofxylene to give, after two recrystallizations from isopropyl alcohol, 9.3grams or a 28 percent yield of 4- mandelamido-1,2,4-triazole melting at183-l85 degrees.

Analysis.C-alculated for C H N O C, 55.02; H, 4.62; N (basic), 6.42.Found: C, 55.17; H, 4.49; N (basic), 6.25.

The compound of this example'is an anti-inflammatory agent. Theanti-inflammatory activity of the compound is'tested using amodification of the procedure of Contu, et al., (Rev. Cana-d. Biol.12:40, 1953). A 10 percent suspension of mustard powder is injected intoa rats foot. This produces a gross edema within 30 minutes afterinjection which slowly subsides within 24 hours (acute stage). Duringthe next several days the swelling and inflammation recure (chronicphase). The test compound is administered subcutaneously for 3 daysprior to the test and for 3-5 days after mustard edema. The amount ofedema is determined by measuring the change in volume of a measuredportion of the edematous foot. Controls are run using the same procedureexcept that only normal saline is injected. The volume of the foot ismeasured daily for seven days, and the percentage increase or decreasein edema produced by the test compound is calculated on the basis of thechange in volurne of the The compound, 4- mandelamido-l,2,4-triazole,shows an average decrease in edema of 71 percent in the acute phase andan average decrease of 91 percent in the chronic phase after asubcutaneous dose of 20 milligrams per kilogram of body weight.Cortisone acetate in the same dose produces a decrease in edema of 35percent in the acute phase and a decrease in edema of 45 percent in thechronic phase.

9 Example 5.4-mandelamid0-3,5-dimetl1yl-1,2,

4-triaz0le Essentially as described in Example 3, 25.5 grams (0.23 mole)of 4-amino-3,5-dimethyl-1,2,4-triazole is reacted With 33.5 grams (0.22mole) of mandelic acid in 200 milliliters of xylene to give, afterrecrystallization from isopropyl alcohol, 6.3 grams of4-mandelamido-3,5-dimethyl-1,2,4-triazole melting at 211-212 degrees.

Analysis.Calculated for C H N O C, 58.51; H, 5.73; N (basic), 5.68.Found: C, 58.86; H, 5.69; N (basic), 5.60.

Example 6 .2- O-acetylmandelamindo) pyridine Essentially as described inExample 2, 26.6 grams (0.28 mole) of 2-aminopyrimidine is reacted with61.1 grams (0.29 mole) of acetlymandelyl chloride in 250 milliliters ofdry pyridine. The reaction mixture is concentrated in vacuo to leave aresidue which is washed with water and crystallized from ethyl alcoholto give 66 grams or an 87 percent yield of2-(O-acetylmandelamido)-pyrimidine melting at 185-1865 degrees.

Analysis.Calculated for C I-1 N C, 61.97; H, 4.83; N (basic), 5.16.Found: C, 62.19; H, 5.10; N (basic), 5.11.

Example 7.2-(fi-hydroxyplzenethylamino) -pyrimidine A mixture of 23.1grams (0.2 mole) of 2-chloropyrimidine, 28.0 grams (0.2 mole) ofB-hydroxyphenethylamine, 22.2 grams (0.22 mole) of triethylamine and 35milliliters of benzene is heated, with stirring, on the steam-bath for 7hours. The cooled reaction mixture is diluted with approximately 100milliliters of benzene and the triethylamine hydrochloride filtered off.The benzene filtrate is concentrated to .a thick oil WhlCh crystallize-sfrom isopropyl alcohol to give 276 grams or a 64 percent yield of2-(B-hydroxyphenethylarnino)-pyrimidine melting at 92-93 degrees.

Analysis.Calculated for C H N O: N (basic), 6.51. Found: N (basic),6.46.

2 (,B-hydroxyphenethylamino)-pyrimidine hydrochloride, which isrecrystallized from ethyl alcohol, melts at 167-168 degrees.

Analysis.-Calculated for C H ClN O: C, 57.25; H, 5.60; Cl, 14.09. Found:C, 57.45; H, 5.47; Cl, 14.06.

Example 8.-2-(fl-hydroxyphenethylamino)- pyrimidine Using essentiallythe same procedure as described in Example 7, except substitutingpotassium carbonate for triethylamine, there is obtained a 56 percentyield of 2- (,8- hydroxyphenethylamino)pyrimidine melting at 91-92degrees.

Example 9.2-(fl-hydroxyphenelhylamino)- pyrimidine To a boiling solutionof 570 grams (6 moles) of 2- amino-pyrimidine in 3.5 liters of ethylalcohol is added, with stirring, 864 grams (7.2 moles) of styrene oxide.The addition requires 2.5 hours, after which the mixture is stirred andrefluxed for 40 hours. The cooled solution is acidified with an excessof ethereal hydrogen chloride and refrigerated overnight to give 291grams of material melting at 151-158 degrees. Two recrystallizationsfrom methyl alcohol yield 183 grams ofZ-(B-hydroxyphenethylamino)-pyrirnidine hydrochloride melting at 167-169degrees. Admixture with the hydrocholoride salt described in Example 7does not depress the melting point.

Analysis-Calculated for C H CIN O: Cl, 14.09. Found: Cl, 14.12.

Example 10.-2-(,B-hydroxyphenethylamino)- pyrimidine To a boilingsolution of 570 grams (6 moles) of 2- arnino-pyrimidine in 2 liters ofethanol is added 27 milliliters of 37 percent hydrochloric acid (0.3mole) and then,

dropwise with stirring, 864 grams (7.2 moles) of styrene oxide. Thesolution is boiled under reflux for 30 hours, concentrated in vacuo andthe residual oil is heated at to degrees (pot temperature) for 3.5 hourswith a slow evolution of ammonia being noted throughout the heatingperiod. The reaction mixture is dissolved in methanol, the solutionacidified with etheral hydrogen chloride and refrigerated.Recrystallization of the resultant precipitate from methanol .alfords488 grams or a 32 percent yield of the hydrochloride salt ofZ-(B-hydroxyphenethylamino)-pyrimidine melting at 167-169 degrees.Admixture with the product prepared in Example 7 does not depress themelting point.

Example 11 .2- S-hydrOxyp'henethylamina) pyrimidine An ethanol solutionof one equivalent of 2-aminopyrimidine and one equivalent of styrenechlorohydrin is heated under reflux on a steam-bath for 40 hours. Theprecipitated product is recrystallized from methyl alcohol to yield2-(,B-hydroxyphenethylamino)-pyrimidine in the form of the hydrochloridesalt, identical with the hydrochloride salt described in Example 7.

Example 12.2-(,B-hydroxyphenethylamino)- pyrimidine Essentially asdescribed in Example 46, Z-(O-acetylmandelamido)-pyrimidine, produced asset forth in Ex ample 6, is reduced with lithium aluminum hydride toyield 2- (B-hydroxyphenethylamino -pyrimidine.

The compounds of Example 7-12 have utility as interneuronal blockingagents and sedatives. The salt 2-(5- hydroxyphenethylamino)-pyrimidinehydrochloride shows interneuronal blocking activity demonstrated by themeasurement of the flexor reflex and linguomandibular reflex of a dogunder stimulus by an electronic stimulator. A solution of thehydrochloride salt, when administered intravenously to a dog, in a doseof 25 milligrams per kilogram of body weight, causes a complete block ofthe flexor and linguomandibular responses. By comparison, phenyramidoand mephenesin, in the same dosage, cause a 75 percent and 50 percentblock, respectively, of the flexor reflex response and a 90 percent and55 percent block, respectively, of the linguomadibular reflex response.

The sedative action of the compounds of these examples is illustrated bya test on dogs. When a solution of the drug is administeredintravenously in a dosage of 40 milligrams per kilogram of body Weight,the dogs exhibit a general anesthesia for a period of 6 minutes with anadditional 10 minutes required for recovery. By comparison, thefollowing table shows other commonly used sedative agents and theiraction under similar conditions:

Acute Ave. time (min) of Drug Dose, Route mg./kg.

Anesthesia Recovery Pentobarbital. 35 Intravenous 240 Hydroxydione 50.d0 23 30 Thiopental 40 d0 40 105 In addition, the hydrochloride salthas been used in man, in an intravenous dosage ranging between 200 and400 milligrams, for the induction of anesthesia.

A.nalysis.Calculate-d for C H N O: N (basic), 6.11. Found: N (basic),6.09.

Treatment of a benzene-ether solution of the base with excess etherealhydrogen chloride and recrystallization of the precipitate fromisopropyl alcohol yields Z-(fl-hydroxya-methylphenethylamino)-pyrimidinehydrochloride in the form of colorless crystals melting at 165-166degrees.

Ainialysis.Calculated for C H ClN O: C, 58.78; H, 6.07; Cl, 13.34.Found: C, 58.66; H, 5.98; Cl, 13.15.

The compounds of this example have utility as interneuronal blockingagents. Central nervous system depression is further illustrated by adecrease in voluntary or stimulated motor activity.

A solution of the salt, 2-(fi-hydroxy-oi-methylphenethylamino)pyrimidine hydrochloride, when administered intravenously to dogs in adose of 10 milligrams per kilo gram of body weight produces a 70 percentdecrease of the flexor reflex response and a 34 percent decrease of thelinguomandibular reflex response.

The central nervous system depressant properties are further illustratedby motor activity tests on mice using a modified method of Dews (Brit.J. Pharmacol. 8:46 (1953)). The number of movements of the mice afteradministration of the drug, as compared to the untreated mice, isreflected in a ratio (R indicating voluntary motor activity. Anothermethod is to administer a central nervous system stimulant to theanimals and then to administer the drug being tested. The ratio of theactivity of the stimulated, treated mice to that of the stimulated,untreated mice is expressed by the value (R indicating stimulated motoractivity. With either ratio, if the R value is greater than 1, the miceare considered stimulated, and if less than 1, they are considereddepressed. The hydrochloride salt of this example produces a value R of0.5 after an intraperitoneal dose of 50 milligrams per kilogram of bodyweight and a value for R of 0.6 after a dose of 25 milligrams perkilogram of body weight. By comparison, meprobamate, with the same dose,gives an R value of 0.9 and in a dose of 100 milligrams per kilogram ofbody weight produces an R value of 0.3.

Example 14.2- (,B-hydroxy-B-ethylphenethylamino) pyrimidine Using themethod of Example 7, 2-cl1loropyrimidine is reacted With,B-hydroxy-fi-ethylphenethylamine to yield 2- (fi-hydroxy ,9ethylphenethylamino)-pyrimidine which melts at 141 degrees.

Almilysis.Calculated for C14H17N3OZ N (basic), 5.76. Found: N (basic),5.79.

The hydrochloride salt, which is prepared in the same manner as inExample 7, melts at 155-156 degrees.

Ainialysis.Calculated for C H ClN O: C, 60.08; H, 6.48; Cl, 12.67.Found: C, 60.73; H, 6.37; Cl, 12.61. 12.33

Example 15.2- (ii-11ydraxy-mfi-diplienylethylamina pyrimidine Using themethod of Example 8, 2-chloropyrimidine is reacted with,G-hydroxy-fi,fi-diphenylethylamine to yield2-(B-hydroxy-;3,B-diphenylethylamino)-pyrimidine which melts at 202-203degrees.

Analysis-Calculated for C H N O: N (basic), 4.81. Found: N (basic),4.79.

The hydrochloride salt, which is prepared in the same manner as inExample 7 melts at 215 degrees.

Awialysis.Calculated for C H ClN O: C, 65.94; H, 5.53; Cl, 10.82. Found:C, 66.35; H, 5.75; CI, 10.77.

The compounds of this example have utility as interneuronal blockingagents and sedatives. A solution of the salt,Z-(B-hydroxy-flfidiphenylethylamin-o)-pyrimidine hydrochloride, in anintraveneous dose of rnilligrams per kilogram of body weight, causes adecrease of 65 percent and 50 percent respectively of the flexor andlinguomandibular reflex responses of the dog.

The sedative action of the compounds of this example is demonstrated inthe same manner as that shown for the compounds of Examples 7-12. Anintravenous dose of 30 milligrams per kilogram of body weight producessleep for a period of 30-40 minutes in dogs.

Example 1 6 .-2 B-hydroxy-B, [3-b is- (4 -m-eth.oxy phenylethylamin0-1-pyrimidine A mixture of 10.4 grams (0.09 grams (0.09 mole)of 2chloropyrimidine, 22.9 grams (0.08 mole) of fl-hydroxydfi-bis-(4-methoxyphenyl)-ethylamine, 10 grams (0.1 mole) oftriethylamine and 65 milliliters of toluene is heated at reflux for 5hours. The precipitate of triethylamine hydrochloride is removed byfiltration, the toluene filtrate concentrated in vacuo and the residuecrystallized from isopropyl alcohol to give 19.1 grams, or a 65 percentyield of2-[fi-hydroxy-l3,/3-bis-(4-methoxyphenyl)-ethylamino]-pyrimidine meltingat 120-121 degrees.

Amalysis.Calculated for C H N O C, 68.36; H, 6.02; N (basic), 3.99.Found: C, 68.45; H, 6.17; N (basic), 3.98.

2-[fl-hydroxy-AB-bis-(4-methoxyphenyl) ethylamino]- pyrimidinehydrochloride is prepared in a cold ethanolether mixture. The product,which is recrystallized, without warming, from an ethanol-ethersolution, melts at 123-124 degrees.

Analysis.Calculated for C H CIN O C, 61.93; H, 5.72; Cl, 9.14. Found: C,61.91; H, 5.60; Cl, 9.12.

Example 17.2-(5,3-dihydr0xyphenetlzylamina)- pyrimidine Using the methodof Example 7, 2-chloropyrimidine is reacted with5,3dihydroxyphenethylamine to yield 2-(,8,3-dihydroxyphenethylamino)-pyrimidine which is isolated in the form of thesolid hydrochloride salt.

Example 1 8.2- ,8-hydroxy-4 -ch loroph enetlz y lamina 7 pyrimidineUsing the method of Example 9, 4-chlorostyrene oxide is reacted withZ-aminopyrimidine to yield Z-(fi-hydroxy-4-chlorophenethylamino)pyrimidine which is isolated in the form of thesolid hydrochloride salt.

Example 19.-2-(,B-hydroxy-4-meth0xyphenethylamina) pyrimidineEssentially as described in Example 16, B-hydroxy-4-methoxyphenethylamine is reacted with 2chloropyrimidine to give2-(B-hydroxy-4-methoxyphenethylamino)- pyrimidine melting at 101-103degrees.

Analysis.Calculated for C H N O N (basic), 5.71. Found: N (basic), 5.67.

2 (B hydroxy 4 methoxyphenethylamino) pyrimidine hydrochloride, which iscrystallized from isopropyl alcohol, melts at 143-144 degrees.

Analysis.Calculated for C I-I ClN O C, 55.41; H, 5.72; Cl, 12.58. Found:C, 56.12; H, 5.92; Cl, 12.51.

The compounds of this example have utility as interneuronal blockingagents. Central nervous system depression is further illustrated by adecrease in stimulated motor activity. A solution of salt,2-(B-hydroxy-4- methoxyphenethylamino)-pyrimidine hydrochloride, uponintravenous administration of 20 milligrams per kilogram of body weight,causes a :percent decrease of the flexor reflex response of a dog and a50 percent decrease of the linguornandibular reflex response.

The central nervous system depressant properties of the compounds isfurther reflected in their ability to depress stimulated motor activity.A solution of the salt, 2 (,8 hydroxy 4 methoxyphenethylamino)pyrimidine hydrochloride, by the same test as shown in Example 13produces an R value of 0.61 after a dose of 25 milligrams per kilogramof body Weight.

Example 20.2- (fi-hydroxy-3,4-dichl0r0phenetlzylamin0)-pyrimidine Usingthe method of Example 16, fl-hydroxy-3,4-dichlorophenethylamine isreacted with 2chloropyrimidine,

13 to give 2 (,6 hydroxy 3,4 dichlorophenethylamino)- pyrimidine meltingat 138-140 degrees.

Analysis.-Calculated -for C H CI N N (basic), 5.22. Found: N (basic),4.84.

2 (,8 hydroxy 3,4 dichlorophenethylamino) pyrimidine hydrochloride,which is crystallized from alcohol, melts at 198-199 degrees.

Analysia-Calculated for C H Cl N C, 44.95; H, 3.77; Cl, (ionic) 11.05;Cl, (total) 33.19. Found: C, 44.31; H, 3.67; CI, (ionic) 11.00; Cl,(total) 32.95.

Example 21 (A) 2-chl0r0-4-trichloromethylpyrimidine.-A mixture of 50.0grams (0.34 mole) of 2-hydroxy-4-methylpyrimidine hydrochloride, 104grams (0.5 mole) of phosphorus pentachloride and 100 milliliters (1.1moles) of phosphorus oxychloride is heated in an oil-bath at 145-155degrees for 7.5 hours, with stirring. The mixture is decanted from sometar-like material and the excess phosphorus oxychloride removed atsteam-bath temperature under moderate vacuum. The dark residue is pouredon cracked ice and extracted with ether. Drying and removal of the etherleaves an amber oil that is distilled to give 26.7 grams or a 34 percentyield of 2-chloro-4-trichloromethylpyrimidine as a colorless oil boilingbetween 102 and 115 degrees at 10 millimeters of mercury pressure. Theoil crystallizes in the form of white needles on cooling and melts onWarming to room temperature, approximately 30 degrees. Uponrecrystallization from hexane, the product melts at 44-46 degrees.

(B) 2 (B hydroxyphenethylamino) 4 trichloromethyZpyrimidine.A mixture of13.7 grams (0.1 mole) of S-hydroxyphenethylamine and 10.1 grams (0.1mole) of triethylamine is stirred while 12.0 grams (0.05 mole) of2-chloro-4-trichloromethylpyrimidine is added. The initial reaction isvery vigorous and cooling is necessary. The mixture is then warmed onthe steam-bath for 0.5 hour and extracted With benzene and chloroform.The triethylamine hydrochloride salt precipitate is removed byfiltration and washed with benzene. The benzenechloroform filtrate,after being washed with 2 percent hydrochloric acid and water, is driedand concentrated in vacuo to give 13 grams of a tan solid, whichcrystallizes from isopropyl alcohol to give 7.5 grams or a 45 percentyield of 2-(B-hydroxyphenethylamino)-4-trichloromethylpyrimidine as awhite powder melting at 109-110 degrees.

Analysis.Calculated :for C H Cl N O: N (basic), 4.22. Found: N (basic),4.03.

2 (B hydroxyphenethylamino) 4 trichloromethylpyrimidine hydrochloride,which is recrystallized from isopropyl alcohol, melts at 180-181degrees. The corrected melting point is 175-176".

Analysis.-Calculated for C H Cl N O: C, 42.31; H, 3.55; Cl (ionic),9.60. Found: C, 42.19; H, 3.52; Cl (ionic), 9.05 (9.69).

Example 22 .2- (fl-hydroxyphenethy lamino -4- am in-5-nitr0-pyrz'midineUsing the method of Example 7, 4-amino-5-nitro-2- chl'oropyrimidine isreacted With /8-hydroxyphenethylamine to yield2-(fl-hydroxyphenethylamino)-4-arnino-5- nitro-pyrimidine Which isisolated in the form of the solid hydrochloride salt.

Example 23.I-(fi-hydroxyphenethylamino 4-methylpyrimidine A mixture of8.5 grams (0.07 mole) of 2-chloro-4- methylpyrimidine, 9.5 grams (0.07mole) of B-hydroxyphenethylamine, 8 grams (0.08 mole) of triethylamineand 50 milliliters of benzene in heated with stirring on the stream-bathfor 7 hours. The precipitated triethylamine hydrochloride is removed,the benzene mother liquor is cooled and ethereal hydrogen chlorideadded. Recrystallization of the resultant precipitate from an isopropylalcohol-ether mixture yields 4.2 grams of 2-(,B-hydroxyphenethylamino)-4-methylpyrimidine hydrochloride melting at139-140 degrees.

Analysis-Calculated for C H ClN O: C, 58.78; H, 6.07; Cl, 13.35. Found:C, 58.96; H, 6.01; Cl, 13.20.

2- B-hydroxyphenethylamino -4-methylpyrimidine, obtained from thehydrochloride salt by treatment with alka- 1i, melts at 70-72 degreesafter crystallization from isopropyl alcohol.

Analysis.Ca1culated for C H N O: N (basic), 6.12. Found: N (basic),5.96.

The compounds of this example have utility as interneuronal blockingagents. A solution of the salt,2-(,8-hydroxyphenethylamino)-4-methylpyrimidine hydrochloride, uponintravenous administration of 20 milligram per kilogram of body weight,causes a 60 percent decrease of the flexor reflex response of a dog anda complete block of the linguomandibular reflex response.

Example 24.2- (B-hya'roxyphenethylamina)-4,6- dimethylpyrimidine Amixture of 18.0 grams (0.13 mole) of 2-chl-oro-4,6- dimethylpyrimidine,16.5 grams (0.12 mole) of ,B-hydroxyphenethylamine, 14.2 grams (0.14mole) of triethylamine and milliliters of toluene is heated at refluxfor 8.5 hours. Work up in a manner similar to that described in Example7 and recrystallization from hexane gives 12.8 grams or a 44 percentyield of 2-(,8 hydroxyphenethylamino)-4,6-dimethylpyrimidine melting at91-93 degrees.

Analysis.-Calculated for C H N O: N (basic), 5.76. Found: N (basic),5.81.

2 (,8 hydroxyphenethylamino) 4,6 dimethylpyrimidine hydrochloride, whichis recrystallized from isopropyl alcoh0lether, melts at 108-110 degrees.

Analysis-Calculated for C H C'lN O: C, 60.10; H, 6.48; CI, 12.68. Found:C, 59.94; H, 6.36; CI, 12.71.

The compounds of this example have utility as interneuronal blockingagents. A solution of the salt, 2-(,B-hydroxyphenethylamino-4,6-dimethylpyrimidine hydrochloride, upon intravenous administrationof 20 milligrams per kilogram of body Weight, causes a 50 percentdecrease of the linguomandibular reflex response of the dog.

Example 25.-2- (fi-hydroxyphenethylam i110 -4- methoxypyrimidineEssentially as described in Example 7, 2-chloro-4-methoxypyrimidine isreacted with fi-hydroxyphenethylamine. The reaction mixture is dissolvedin chloroform and Washed with Water. The dried chloroform solution iscooled, treated with ethereal hydrogen chloride and then diluted withether. The precipitate is recrystallized from isopropyl alcohol-ether toyield Z-(B-hydroxyphenethylamino)-4-methoxypyrimidine hydrochloridemelting at -132 degrees.

Analysis.-Calculated for C H CIN O C, 55.43; H, 5.72; Cl, 12.58. Found:C, 56.12; H, 6.20; Cl, 12.37.

The compound ofthis example has utility as a central nervous systemdepressant as reflected in its ability to decrease motor activity. Asolution of the salt, Z-(B-hydroxyphenethylamino) 4 methoxypyrimidinehydrochloride, by the same test as shown in Example 13, produces an Rvalue of 0.65 after a dose of 50 milligrams per kilogram of body weightan R value of 0.80 after a dose of 25 milligrams per kilogram of bodyweight.

Example 26.2- (fl-hydroxyphene'zhylamino)-5- chloropyrimidine Using themethod of Example 16, 2,5-dichloropyrimidine is reacted withfl-hydroxyphenethylamine to yield 2 (5 hydroxyphenethylamino) 5chloropyrimidine melting at 123-124 degrees.

Analysis.Calculated for C H ClN O: N (basic), 5.62; Cl, 14.20. Found: N(basic), 5.11; CI, 14.18.

2 (,8 hydroxyphenethylamino) 5 chloropyrimidine Example27.2-(B-hydroxyphenelhylamino)-4- pyrimidinecarboxylic acid A solutionof 17.0 grams (0.1 mole) of silver nitrate in 40 milliliters ofdeionized water is added to a solution of 6.6 grams (0.02 mole) ofZ-(fi-hydroxyphenethylamino)-4-trichloromethylpyrimidine in 75milliliters of glacial acetic acid. The mixture is heated on a steambathfor 2 hours, the precipitate of silver chloride is removed byfiltration, and the filtrate is diluted with 600 milliliters ofdeionized water to precipitate 4.5 grams of the silver salt of2-(,B-hydroxyphenethylamino)-4-car boxylic acid. The salt is suspendedin 20 milliliters of warm ethanol, hydrogen sulfide is bubbled into themixture, and the silver sulfide precipitate is removed by filtration.The ethanol filtrate is cooled, and the resultant yellow precipitate isrecrystallized from ethanol to give 1.5 grams or a 29 percent yield of2-( 3-hydroxyphenethylamino)-4-pyrimidinecarboxylic acid melting at 203-205 degrees.

Analysis.Calculated for C H N O C, 60.22; H,

5.05; N (basic), 5.40. Found: C, 60.28; H, 5.03; N

(basic), 5.31.

Example 28.--2-[fi-(N-ethylcarbamyloxy)-phenethylamin01-pyrimidine To asolution of 8.0 grams (0.04 mole) of the product described in Example 7,in 10 milliliters of benzene, is added 5.7 grams (0.08 mole) of ethylisocyanate and the mixture is warmed on the steam-bath for 1 hour. Thesolid mixture, after recrystallization from benzene, gives 6.6 grams ora 63 percent yield of 2-[,8-(N-ethylcarbamyloxy)-phenethylamino]-pyrimidine melting at 164-165 degrees.

Analysis.Calculated for C H N O 4.89. Found: N (basic), 4.84.

Treatment of an ethyl acetate-benzene solution of the base with excessethereal hydrogen chloride and concentration in vacuo leaves a yellowoil, which crystallizes from isopropyl alcohol-ether to give2-[5-(N-ethylcarbamyloxy) phenethylamino] pyrimidine hydrochloridehemihydrate in the form of a hygroscopic white powder melting at 101-103degrees.

Analysis-Calculated for C H ClN O /2H O: C, 54.30; H, 6.08; Cl, 10.69; HO, 2.7. Found: C, 53.72; H, 5.82; Cl, 10.40; H O, 4.2.

The compounds of this example have utility as analgesics, interneuronalblocking agents, and also possess other central nervous systemdepressant effects. A solution of the salt,2-[B-(N-ethylcarbamyloxy)-phenethylamino]-pyrimidine hydrochloride, whenadministered to mice in a dose of milligrams per kilogram of bodyweight, increases the reaction time 38 percent to pain produced byradiant heat On the hind foot of the mouse.

A solution of the hydrochloride salt, when administered intravenously todogs in a dose of 20 milligrams per kilogram of body weight, produces acomplete block of both the flexor reflex and linguomandibular reflexresponses.

The central nervous system depressant properties of the compounds inthis example are further illustrated by the motor activity in mice.Using the same tests as shown in Example 13, a solution of thehydrochloride salt, in intravenous doses of 50 milligrams. per kilogramof body weight, produces an R value of 0.7 and, in doses of 25milligrams per kilogram, produces an R value of 0.5.

N (basic),

Example 29.-2-(B-hydroxyphenethylamino)pyrimidine hemisuccinate To amixture of 25.2 grams (0.1 mole) ofZ-(B-hydroxyphenethylamino)-pyrimidine hydrochloride in 75 millilitersof dry pyridine is added 10.1 grams (0.1 mole) of succinic anhydride.The mixture is stirred overnight at room temperature, heated on asteam-bath for one hour and the pyridine is removed in vacuo to leave atan solid residue. The residue is crystallized from isopropyl alcohol toyield 23.5 grams or a 74 percent yield of 2- (fi-hydroxyphenethylamino)pyrimidine hemisuccinate melting at 162-163 degrees.

Analysis.Calculated for C H N O C, 60.96; H, 5.43; N, 4.44. Found: C,61.04; H, 5.34; N, 4.42.

Example 30.-2-(ti-butyroxyphenethylamino)-pyrimidine To a solution of15.2 grams (0.07 mole) of Z-(fi-hydroxyphenethylamine)-pyrirnidine and9.0 grams (0.09 mole) of triethylamine in 150 milliters of dry tolueneis added, dropwise with stirring and intermittent cooling, 8.6 grams(0.08 mole) of n-butyryl chloride. The reaction mixture is stirred atroom temperature for 4 hours, the precipitate of triethylaminehydrochloride is removed by filtration and the toluene filtrateconcentrated in vacuo to leave a tan solid residue. The residue iscrystallized from isopropyl alcohol to give 14.9 grams of a 75 percentyield of 2-(fl-butyroxyphenethylamino)-pyrimidine melting at 93-85degrees.

Analysis.Calculated for C H N O N (basic), 4.91. Found: N (basic), 4.90.

2-(fl-butyroxyphenethylamino) pyrimidine hydrochloride is obtained fromisopropyl alcohol-ether as a hygroscopic solid.

Analysis-Calculated for C H ClN O C, 59.72; H, 6.26; Cl, 11.01. Found:C, 59.54; H, 6.54; Cl, 10.71.

The compounds of this example have utility as interneutronal blockingagents. A solution of the salt 2-(5- butyroxyphenethylamino)-pyrimidinehydrochloride, upon intravenous administration of 20 milligrams perkilogram of body weight, causes a complete block of both thelinguomandibular and flexor reflex responses.

Example 31.-2-(B-farmoxypyhenethylamino)- pyrimidine A solution of 50.0grams of Z-(fi-hydroxyphenephyl- -amino)-pyrimidine in 90.0 milliltersof 98 percent formic acid is heated on the steam-bath for four hours.The reaction mixture is concentrated in vacuo to leave an oil whichsolidifies when triturated with ice water. The solid is recrystallizedfrom isopropyl alcohol to give 30.0 grams or a 54 percent yield of2-(B-form-oxyphenethylamino)-pyrirnidine melting at 113-114 degrees.

Analysis.Calculated for C H N O N (basic), 5.76. Found: N (basic), 5.75.

2-(,B-formoxyphenethylamino) pyrimidine hydrochloride; which isrecrystallized from isopropyl alcohol and then from ethyl acetate, meltsat 115-117 degrees.

Analysis.Ca1culated for C H ClN O C, 55.82; H, 5.04; Cl, 12.68. Found:C, 56.38; H, 5.47; Cl, 12.80.

Example 32.-2-(fl-acetoxyphenethylamina)-pyrimidine Using the method ofExample 30, Z-(fi-hydroxyphenethylamino)-pyrimidine is reacted withacetyl chloride to give 2-(B-acetoxyphenethylamino)-pyrimidine meltingat 123-124 degrees.

Analysis.-Calculated for C H N O N (basic), 5.45. Found: N (basic),5.31.

Example 33.2-[fl-(eth0xyf0rm0xy)-phenethylamino]- pyrimidine Using themethod of Example 30, Z-(B-hydroxyphenethylamino)-pyrimidine is reactedwith ethyl chloroformate to give 2-[fi-(ethoxyformoxy)-phenethylamino]-pyrimidine melting at -106 degrees.

Analysis.-Calculated for C H N O N (basic), 4.88. Found: N (basic),4.88.

Z-[fi-(ethoxyformoxy) phenethylamino] -pyrirnidine hydrochloride, afterrecrystallization from isopropyl alcohol, melts at 127-130 degrees.

17 Analysis.-Calculated for C H ClN O C, 55.62; H, 5.60; Cl, 10.95.Found: C, 55.27; H, 5.68; Cl, 10.97.

The compounds of this example have utility as interneuronal blockingagents. A solution of the salt, 2-[5- 18 Example 36 .-4-( 3-hdroxyphenethylamino)- 2-pyrimidinethi0l A mixture of 44.0 grams (0.32mole) of p-hydroxyphenethylarnine and 21.6 grams (0.15 mole) of 2,4-py-(ethoxyformoxy)'Phenethylamino]'Pyrimidme hycirochlo' 5 rimidinedithiolis heated in an oil-bath at 120 degrees for ride upon administration of20 mflhgrams per kllogram 2.5 hours. The semisolid residue is trituratedwith benof body weight, causes a 50 percent decrease of the fiexor Ruethe bgnze'n'e decanted the residue is h {eflex respqnse of the dog and acomplate block of the turat ed with acetone. 7 The solid is collected togive 31. 8 lmguomandlbular reflex response grams or an 86 percent yieldof 4-(fl-hyd-roxyphenethyl- 10 amino -2- r'midi ethiol melti at1'91.-193 de rees. Example 34.2-.[13:(etlzylthi0lform0xy)-phenethyl-Analysiii Calch lated for l a m so 'N l -l-py 5.67. Found: N (basic),5.52. I

4- (,e-hydroxyphenthylamino 42-pyr-imidinethiol hydro- Usmg. the lExample Lw'hydmxyphFm chloride, which is recrystallized from a mixtureof ethyl ethylamlno)-pyrlmldlne is reacted with ethyl chlorothlolandmethyl alcohol melts at 207409 degrees formate to give 2 [,8(ethylthiolformoxy) phenethyl- Analysis i for'c H i 50 Hamino]-pyrimidine melting at 111112 degrees. C1 50 Found, C 5 8 g 1 iAnalysis.Calculated for C15H17N302SI N (basic), 4.62. Found: N (basic),4.61. Example 37.4-(,B-hydroxyphenethylamino)-2-[B-(ethylthiolformoxy)-phenethylamino] pyrimidineZ-methylthiopyrimidine hydrochloride, after recrystallization fromisopropyl allDimethyll Sulfate, 16.5 grams (0J3 mole), is added coholmelts at 138-140 degrees with stirring to a solution of 31.0 grams (0.12mole) of Analysls' calculated for C15H18C1N3O2S' the compound obtainedin Example 36 in 200 milliliters 534; 10'439 Found: 53'62; of watercontaining 5.2 grams (0.13 mole) of sodium by- 1036; droxide. Themixture is stirred for -1.5 hours and the The compounds of thl's example.have unhty as precipitated product filtered off, washed with water andtemfiurqnal blockmg A splutlon i fl recrystallized from isopropylalcohol to give 25.0 grams (ethylthlolformoliy)'phenethylamln9] pynmldmefq' or an 80 percent yield of 4-(fl-hydroxyphenethylamino)- chloride,upon intravenous administration of 20 mllllzmethylthiopyrimidine asWhite crystals melting at grams per kilogram of body weight, causes a 50percent 30 126 degrees. decrease of the flexor reflex response of a dogand 75 Analysis ca\lculated for C H N (basic) percent decrease of thelinguomandibular reflex response. 5 36. N 5 33 l5 3 t4-(fl-hydroxyphenethylamino) Z-methylthiopyrimidine Example35-3-(2-Py"lm1dyl)Jehenylomzohdme 35 hydrochloride, which isrecrystallized from ethyl alcohol,

melts at 209 degrees.

A mlxtureof m mole) of B- Y Analysis-Calculated for C H ClN OS: c,52.43; H, phenethylamlno)-pyrlrnldlne, 3.0 grams (0.1 m l of 5.41; C1,1190. Found: C, 52.72; H, 5.38; Cl, 11.93. paraformaldehyde and 150milliliters of toluene is boiled under reflux in a flask fitted wih aDean-Stark water trap Example (fi' l h f for 3 hours. The toluenesolution is concentrated in 40 z'pynmldmol vacuo to leave a colorlessoil which crystallizes from Hydrogen peroxide, 30 percent, in the amountof 15 heXanB t0 give grams or an 86 Pfifceht Yield of grams (0.13 mole),is added dropwise with stirring to a py idyl)- -P ny1 X melting atdegrees cooled solution of 9.3 grams (0.04 mole) of 4-(,8-hy

Analysis--chlchlfiled for la la s N droxyphenethylamino) 2methylthiopyrimidine in 100 Found! N milliliters of acetic acid. Thesolution is allowed to stand -PY dY 5 Phenyloxazohdme y l for 5 days atroom temperature, the mixture is diluted after recrystallization fromisopropyl alcohol, melts at with ether d an ss of ethereal hydrogenchloride 146449 degreesis added to precipitate a yellow oil which cannotbe crys- A"l1l)Sl'S--Ca1Cl-l1ated ls n s C, tal-lized. An aqueoussolution of the hydrochloride salt 53 C1, Found! is treated with solidpotassium carbonate and the resultant The compounds of this eXaIhP1ehave utility as interprecipitate recrystallized 3 times from a mixtureof methyl neuronal blocking agents- A Solution of the Salt, and ethylalcohol to give 1.2 grams of 4-(;3-hydroxyphenepy y )'5P yhydrochloride, p thylamino)-2-pyrimidinol melting at 218-2119 degrees.travenous administration of .10 milligrams per kilogram Analysis,calculated fpr 3 11 10 0 1c 6233; of body weight, causes an .85 percentdecrease of the o 566; N (basic), 6.04, Found: C, 61.89; H, 5.78; Nflexor reflex response of the dog and a complete block (b ic), 6,01, ofthe linguomandibular reflex response. The compounds ,of Examples 36 3-8show the follow- The sedative action of the compounds of this exampleing pharmacological activities:

Intel-neuronal Block percent Percentincrease decrease after a 20 mgJkg.

I in reaction intravenous dose Motor Activity, Motor Activity, ExampleDose mg./kg. tlrnettp pal niul 50 mg./kg. R}, 25 mg./kg. R

S mu 1 Flexel' Reflex Linguoman Reflex 35 5Intravenous 0 0.7 0.7 37 do10 0.5 0.6 38 20Intraper1- 39 toneal.

is demonstrated in the same manner as that shown for the compounds ofExamples 7'1i2. An intravenous dose of 50 milligrams per kilogram ofbody weight produces sleep for a period of 5-7 minutes in dogs.

Example 39.4-(fl-hydroxyphenethylamino)-pyrimidine A stirred mixture of10.0 grams (0.04 mole) of 4-(5- hydroxyphenethylarnino)Z-methylthiopyrimidine, pre- 5 pared as described in Example 37, 15teaspoonsful of Raney nickel catalyst (W-2) and 150 milliliters of ethylalcohol is heated on the steam-both for 4 hours. The filtered solutionis concentrated in vacuo to a white intractable gum which is convertedto the hydrochloride salt and recrystallized twice from isopropylalcohol to give 4.6 grams or a 56 percent yield of4-(B-hydroxyphenethylamino)-pyrimidine hydrochloride as colorless platesmelting at 169-170 degrees.

Analysis.-Calculated for C H clNgO: C, 57.25; H, 5.60; Cl, 14.09. Found:C, 56.67; H, 5.52; 01, 14.05.

Compounds of this example have utility as analgesic agents. A solutionof the salt, 4- (,B-hydroxyphenethylamino)-pyr'unidine hydrochloride, inan intravenous dose of 5 milligrams per kilogram of body weight,increases the reaction time by 26 percent to pain produced by radiantheat on the hind foot of the mouse.

Example 40.4-(fl-hydroxyphenethylamino)- Z-aminopyrimidine A mixture of8.0 grams (0.06 mole) of 2-amino-4-chloro-pyrimidine, 9.0 grams (0.06mole) of fi-hydroxyphenethylamine and 7.0 grams (0.07 mole)triethylamine in 50 milliliters of ethyl alcohol is heated on thesteam-bath for 8 hours. The mixture is allowed to cool overnight in arefrigerator after which 1.2 grams of white solid melting at 240-300degrees is filtered off. The filtrate is concentrated in vacuo on thesteam-bath leaving a yellow oil. The oil is dissolved in dilutehydrochloric acid, washed with ether, cooled and made basic with 20percent sodium hydroxide. The resulting precipitate is collected on afilter, washed with water and recrystallized from isopropyl alcohol togive 5.6 grams, or a yield of 40 percent, of 4-(fihydroxyphenethylamino)-2-aminopyrimidine melting at 151-152 degrees.

Analysis.-Calculated for C H N O: N (basic), 6.08. Found: N (basic),6.10.

4 (B-hydroxyphenethylamino)-2-aminopyrimidine hydrochloride, which isrecrystallized from isopropyl alcohol, melts at 177-178 degrees.

Analysis.-Calculated for C H ClN O: C, 54.04; H, 5.67; Cl, 13.30. Found:C, 54.31; H, 5.25; Cl, 13.26.

Example 41 .-2- B-hydroxyphene thylamino 3-methylpyrazine A mixture of18.0 grams (0.14 mole) of 2-chloro-3- methylpyrazine, 18.0 grams (0.13mole) of fl-hydroxyphenethylamine, 23.2 grams (0.14 mole) of potassiumcarbonate and 0.5 gram of copper powder is heated in an oil-bathmaintained at 160 degrees for 7 hours. The mixture is extracted withbenzene, the benzene solution is concentrated and the residue isdistilled to give 8.3 grams or a 28 percent yield ofZ-(fl-hydroxyphenethylamino)-3-methylpyrazine that distills between 195and 201 degrees at 0.5 millimeter of mercury pressure.

Analysis.Calculated for C H N O: N (basic), 6.11. Found: N (basic),6.06.

2 (B hydroxyphenethylamino) 3 methylpyrazine hydrochloride formscolorless crystals from isopropyl alcohol-ethyl acetate melting at111-113 degrees.

The compounds of this example have utility as interneuronal blockingagents. A solution of the salt,Z-(B-hydroxyphenethylamino)-3-methylpyrazine hydrochloride, uponintravenous administration of a dose of 20 milligrams per kilogram ofbody weight, causes a complete block of the flexor and linguomandibularreflex responses.

Example 42.3-(p-hydroxypheneihylamino 6 -ch loropyridazine A mixture of38 grams (0.25 mole) of 3,6-dichloropyridazine, 36 grams (0.26 mole) ofB-hydroxyphenethylamine and 27.5 grams (0.27 mole) of triethylamine in200 milliliters of ethanol is heated in an autoclave at 150 degrees forhours. The, ethanol solution is concentrated in vacuo. The residue istriturated with water and recrystallized from isopropyl alcohol to give23.3 grams 20 or a 37 percent yield of 3-(fi-hydroxyphenethylamino)-6-chloropyridazine melting at 149-150 degrees.

Analysis.-Calculated for C H ClN O: N (basic), 5.61. Found: N (basic),5.51.

3- (fl-hydroxyphenethylamino -6-chloropyridazine hydrochloride, afterrecrystallization from ethyl alcohol, melts at 185-186 degrees.

Analysis.Calculated for C H Cl N O: C, 50.35; H, 4.58; Cl (ionic),12.39. Found: C, 50.67; H, 4.65; Cl (ionic), 12.37.

Example 43 .3- fi-hydroxy ph enethylamino) pyridazine A stirred mixtureof 15.0 grams (0.06 mole) of 3-( 8-hydroxyphenethylamino)-6-chloropyridazine, 2 grams of 10 percentpalladium on carbon and 25 milliliters of 64 percent hydrazine in 200milliliters of ethyl alcohol is boiled on the steam-bath for 1.5 hours.The cooled mixture is filtered and the filtrate concentrated to leave atan solid. The solid is washed with water and crystallized from anisopropyl alcohol-water mixture to give 8.8 grams or a 68 percent yieldof 3-(j8-hydroxyphenethylamino)-pyridazine melting at 141-142 degrees.

Analysis.Calculated for C H N O: N (basic), 6.51. Found: N (basic),6.50.

.3 ([3 hydroxyphenethylamino) pyridazine hydrochloride, afterrecrystallization from isopropyl alcohol, melts at 122-124 degrees.

Analysis.-Calculated for C H C1N O: C, 57.25; H, 5.60; CI, 14.09. Found:C, 57.53; H, 5.50; Cl, 14.08.

The compounds of this example have utility as analgesic agents. Asolution of the salt, 3-(l3-hydroxyphenethylamino) pyridazinehydrochloride, in an intravenous dose of 5 milligrams per kilogram ofbody weight, increases the reaction time by 27 percent to pain producedby radiant heat on the hind foot of the mouse.

Example 44 .2- B-hydroxy phenethylamino) -s-triazine A mixture of 13.8grams (0.05 mole) of fl-hydroxyphenethylguanidine hydrobromide, 4.2grams (0.05 mole) of s-triazine and 25 milliliters of absolute ethanolis boiled for 20 hours on the steam-bath. The precipitated solid isrecrystallized from methanol to give 4.3 grams or a 40 percent yield of2-(B-hydroxyphenethylamino)-striazine melting at 211-212 degrees.

Analysis.-Calculated for C H N O: C, 61.10; H, 5.60; N (basic), 6.48.Found: C, 61.46; H, 5.88; N (basic), 6.45.

The compound of this example has utility as an antiinfiammatory agent.Using the same procedure as described in Example 4,2-(B-hydroxyphenethylamino)-s triazone in a subcutaneous dose of 20milligrams per kilogram of body weight produces an average decrease inedema of 47 percent in the acute phase and an average decrease in edemaof 49 percent in the chronic phase.

Example 45 .2-( fi-hydroxyphenethylamino)- 4,6-diamino-s-triazine To aslurry of 72.8 grams (0.5 mole) of 2,4-diamino- 6-chloro-s-triazine in500 milliliters of water is added 71.3 grams (0.52 mole) ofB-hydroxyphenethylamine. The slurry is stirred and heated to -95 degreesand a solution of 74.4 grams (0.6 mole) of monohydrated sodium carbonatein milliliters of warm Water is then added dropwise over a period of onehour. The reaction mixture is stirred and heated for an additional 3hours, cooled to 15 degrees and filtered. The filter cake is washed withcold water and dried in a vacuum oven at 80 degrees for 4 hours to yield123 grams of material. The product is recrystallized four times fromethanol to yield 66.7 grams or a 54.3 percent yield ofZ-(B-hydroxyphenethylamino)-4,6-diamino-s-triazine melting at 176-178degrees.

Analysis.Calculated for C H H O: C, 53.64; H,

21 5.73; N (basic), 5.90. Found: C, 54.00; H, 5.83; N (basic), 5.60.

The compound of this example has utility as an antiinflammatory agent.Using the same procedure as described in Example 4,2-(,B-hydroxyphenethylamino)-4,6- diamino-s-triazine produces an averagedecrease in edema of 45:11 percent in the acute phase and an averagedecrease in edema of 67:14 percent in the chronic phase after asubcutaneous dose of 20 milligrams per kilogram of body weight. Thecompound also produces an average decrease in edema of 26:4 and 44:8percent during the acute and chronic phases of the test procedurerespectively, after an oral does of 75 milligrams per kilogram of bodyweight. By comparison, penylbutazone, in the same dosage, produces anaverage decrease in edema of 39:6 and 65:3 percent during the acute andchronic phases of the test procedure, respectively.

Example 46.-2-(B-hydmxyplzenethylamina)-thiaz0le A solution of 35.6grams (0.13 mole) of Z-(O-acetylmandelamido)-thiazole (Example 1) in 200milliliters of ethylene glycol dimethyl ether is added, dropwise to astirred slurry of 11.5 grams (0.3 mole) of lithium aluminum hydride in300 milliliters of ethylene glycol dimethyl ether. The addition requires1.5 hours, after which the mixture is refluxed for 30 minutes, cooledand the excess lithium aluminum hydride decomposed by the addition of 30milliliters of ethyl acetate. Seventy-five milliliters of water is addeddropwise, the precipitate of aluminum hydroxide is removed byfiltration, and the filtrate concentrated to give a thick yellow oilwhich solidifies on cooling. The crude product is crystallized fromisopropyl alcohol to give 20 grams or a 70 percent yield of 2-(,B-hydroxyphenethylamino)-thiazole melting at 9697 degrees.

Analysis.calculated for C11H12N2OS: N (basic), 6.36. Found: N (basic),6.32.

2- B-hydroxyphenethyl amino -thiazole hydrochloride, afterrecrystallization from isopropyl alcohol, melts at 161162 degrees.

Analysis-Calculated for C H ClN OS: C, 51.43; H, 5.10; Cl, 13.80. Found:C, 52.18; H, 5.35; Cl, 13.74.

The compounds of this example are interneuronal blocking agents, centralnervous system stimulants and anorexigenic agents. A solution of thesalt, Z-(fi-hydroxyphenethylamino)-thiazole hydrochloride, uponintravenous administration to dogs in a dose of 25 milligrams perkilogram of body weight produces a complete block of the flexer reflexresponse and a 50 percent decrease in the linguomandibular response.

The central nervous system stimulant properties are illustrated by theeffect of the compounds on motor activity. A solution of the salt,Z-(fi-hydroxyphenethylamino)-thiazole hydrochloride, using the testprocedure outlined in Example 13 produces an R value of 1.5 and an Rvalue of.1.78.

The anorexigenic activity is measured using dogs as test animals bycomparing food intake with and without drug. The compound reduces foodintake by 46 percent during a day test period with an oral dose of 5milligrams per kilogram of body weight.

Example 47 .4-(fi-hydroxyphenethylamino)J,2,4-

triazole 4-amino-1,2,4-triazole, 20.2 grams (0.24 mole), is added, insmall portions, to a stirred mixture of 10.2 grams (0.26 mole) of sodiumamide in 200 milliliters of liquid ammonia. After the addition iscomplete, the mixture is stirred for 30 minutes and 29 grams (0.24 mole)of styrene oxide is added dropwise to the stirred reaction mixture. Asthe liquid ammonia evaporates, it is replaced with ethylene glycoldimethyl ether. In about 3 hours the reaction mixture becomesexceedingly thick and can no longer be stirred. The ethylene glycoldimethyl ether is decanted, the residual gum is dissolved in 5 percenthydrochloric acid and the solution washed with ether. The cold aqueousacid layer is made basic with 20 percent sodium hydroxide, and saturatedwith potassium carbonate to precipitate a brown solid. The precipitateis washed with a small amount of ice water and recrystallized twice fromisopropyl alcohol to give 9.3 grams or a 19 percent yield of4-(13-hydroxyphenethylamino)-1,2,4-triazole melting at 137-141 degrees.

Analysis.Calculated for C H N O': C, 58.82; H, 5.93; N (basic), 6.86.Found: C, 58.84; H, 6.05; N (basic), 6.80.

Example 48.-4- (fi-hydroxyphenethy[amino 1 ,2,4-triazole Essentially asdescribed in Example 46, 4-mandelamido-1,2,4-triazole (Example 4) isreduced with lithium aluminum hydride to yield4-(,B-hydroxyphenethylamino)- 1,2,4-triazole, identical with thematerial obtained as described in Example 47.

Example 4 9.3- fl-hydroxy phenethylamino 1,2,4-triazole Essentially asdescribed in Example 46, 3-mandela-mido-1,2,4-triazole (Example 3) isreduced with lithium aluminum hydride in ether to yield3-(fi-hydroxyphenethylamino) 1,2,4-triazole.

Example 50.4-(B-hydroxyphenelhylamino -3,5-dimethyl-1 ,2,4-triaz0leEssentially as described in Example 46,4-mandelamido-3,5-dimethyl-1,2,4-triazole (Example 5) is reduced withlithium aluminum hydride in ether to yield 4-(5- hydroxyphenethylam-ino)-3 ,5 -dimethyl-1,2,4-triazole.

Example 51.-2-( S-hydmxyphenethylamino)-1,3,4-

thiadiazole Essentially as described in Example 46,Z-(O-acetylmandelamido)-1,3,4-thiadiazole (Example 2) is reduced withlithium aluminum hydride in ether to yield 2-(6-hydroxyphenethylamino)-1,3,4-thiadiazole.

The novel compounds of this invention can be combined with solid orliquid pharmaceutical carriers and formulated into the form of tablets,powder packets or capsules or dissolved in suitable solvents for oraland parenteral administration for human and veterinary use.

The invention can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingphysical embodiments are, therefore, to be considered in all respectsillustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

We claim: 1. A chemical compound having the formula OH s-triazine-NCH(3-pheny1 H R R wherein s-triazine is the s-triazine ring attached to thefl-hydroxyphenethylamino moiety by a ring carbon atom, the substituentson the s-triazine and phenyl rings being selected from the groupconsisting of hydrogen, and not more than one halo, lower-alkyl, loweralkoxy, methylenedioxy, amino, nitro, trihalomethyl, hydroxy, mercapto,lower-alkylthio and carboxy, R is selected from the group consisting ofhydrogen, lower-alkyl, benzyl and phenyl and R is selected from thegroup consisting of hydrogen and methyl.

2. N-(s-triazin-Z-yl)-N- 8-hydroxyphenethylamine.

3. 4,6 diamino 2 (,B-hydroxyphenethylamino)-stnazine.

No references cited.

WALTER A. MODANCE, Primary Examiner.

I. M. FORD, Assistant Examiner.

1. A CHEMICAL COMPOUND HAVING THE FORMULA